Antimetabolitit

Antimetabolitit (antimetabolites) are a class of drugs that resemble normal cellular metabolites and disrupt nucleotide synthesis or utilization. They act as metabolic analogs of folate, purines, or pyrimidines, thereby inhibiting DNA and RNA synthesis or function. Most antimetabolites are most active in the S phase of the cell cycle and preferentially affect rapidly dividing cells.

They are commonly subdivided into antifolates (for example methotrexate and pemetrexed), pyrimidine analogs (such as 5-fluorouracil, capecitabine, and cytarabine), and purine analogs (including mercaptopurine, thioguanine, azathioprine, fludarabine, and cladribine). Antifolates inhibit enzymes like dihydrofolate reductase or thymidylate synthase, lowering thymidine and purine pools. Pyrimidine analogs can be incorporated into RNA or DNA or inhibit thymidylate synthase. Purine analogs interfere with purine nucleotide synthesis and function, often being incorporated into nucleic acids.

Clinical use includes cancer chemotherapy for leukemias, lymphomas, colorectal and other solid tumors, and autoimmune diseases such as rheumatoid arthritis and Crohn's disease; some agents are used for immunosuppression in transplantation.

Common toxicities reflect effects on rapidly dividing tissues and include bone marrow suppression, mucositis, hepatotoxicity (notably with methotrexate and 5-FU), and, for some agents, nephro- or neurotoxicity. Resistance may arise from reduced drug uptake, increased drug inactivation, target enzyme changes, or increased DNA repair.

Discovery and development span the mid-20th century, establishing antimetabolites as foundational chemotherapeutic agents.